Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound β1-Adrenergic Receptor. Academic Article uri icon

Overview

abstract

  • Cardiac disease remains the leading cause of morbidity and mortality worldwide. The β1-adrenergic receptor (β1-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by β1-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which β1-AR activates Gs. We find that the tilting of α5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal α5-helix and the backbone carbonyl of Arg38 in the N-terminal αN-helix of Gαs. Together with the disruption of another interacting network involving Gln59 in the α1-helix, Ala352 in the β6-α5 loop, and Thr355 in the α5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.

publication date

  • August 19, 2020

Research

keywords

  • GTP-Binding Protein alpha Subunits, Gs
  • Isoproterenol
  • Receptors, Adrenergic, beta-1

Identity

PubMed Central ID

  • PMC7541785

Scopus Document Identifier

  • 85090205426

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2020.08.001

PubMed ID

  • 32818430

Additional Document Info

volume

  • 80

issue

  • 1